Hepatic ischemia–reperfusion injury: Underlying mechanisms and concepts in liver surgery and liver transplantation

Hepatic ischemia-reperfusion injury (H-IRI) is a critical complication in liver surgery and liver transplantation, contributing to graft dysfunction and poor clinical outcomes. When hepatocyte protective mechanisms are insufficient to counteract energy depletion and oxidative stress during ischemia, cell death occurs. Tissue damage during H-IRI leads to the release of damage-associated molecular patterns (DAMPs), which recruit and activate immune cells such as neutrophils and monocytes, orchestrating the initiation, progression, and eventual resolution of sterile inflammation. Extended criteria donor (ECD) livers, particularly steatotic ones, are more vulnerable to H-IRI, leading to poorer outcomes and limiting expansion of the donor pool. However, the mechanisms underlying this increased vulnerability are not yet fully understood. Emerging therapeutic strategies, including machine perfusion technologies, ischemic preconditioning, pharmacological interventions, and others, offer promise for mitigating H-IRI by either attenuating early injury triggers, enhancing intrinsic survival pathways, or restraining excessive inflammatory responses. Despite considerable progress in understanding H-IRI, further research is needed to identify additional therapeutic targets, particularly in the context of ECD livers, to develop effective, targeted interventions that can improve clinical outcomes.